ライフサイエンスコーパス: ABCG5

1 epG2 cells increased expression of LRH-1 and ABCG5.

2 tein expression, and binding of LRH-1 at the Abcg5/8 and Cyp7a1 promoter was reduced.

3 and the link between the sterol transporters ABCG5/8 and NPC1L1 and intestinal cholesterol absorption

4 Notably, ABCG5/8 and NPC1L1 expression was similar in gallstone c

5 ing or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knock

6 GF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and chole

7 re obtained by suppressing the LRH-1 targets ABCG5/8 by treatment with small interfering RNA, IL-1B,

8 intrinsically linked via the function of the ABCG5/8 cholesterol transporter.

9 In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol abso

10 esterolemia genes and were sequenced for the ABCG5/8 genes.

11 vity, thereby suppressing full maturation of ABCG5/8 transporter.

12 ABCG5/8 variants did not fully explain the sterol metabo

13 Common ABCG5/8 variants were genotyped.

14 ATP binding cassette subfamily G member 5/8 (Abcg5/8) and cluster of differentiation 36 (Cd36), was l

15 ATP binding cassette subfamily G member 5/8 (ABCG5/8) suppression by GSK2033 increased the accumulati

16 ber 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol level

17 Ppargamma, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIgamma), an

18 ATP-binding cassette subfamily G members 5/8(Abcg5/8); and normalized serum bile acids.

19 acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipid

20 on, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calc

21 est the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and

22 Genetic variation in ABCG5/8, which associates with decreased levels of plasm

23 Mice homozygous for disruption of Abcg5 (Abcg5(-/-) ) or Lxra (Lxra(-/-) ) and their wild-

24 ctase, and the cholesterol efflux genes (eg, ABCG5, ABCG8).

25 including ABCC3, ABCB6, ABCD1, ABCG1, ABCG4, ABCG5, ABCG8, ABCE1, ABCF1, ABCF2, and ABCF3, were expre

26 sion of cholesterol metabolism related genes Abcg5, Abcg8, Abcg11, Cyp7a1 and Cyp8b1; and (6) induced

27 with downregulation of hepatic expression of ABCG5, ABCG8, and ABCB11 biliary transporters.

28 The ABCG1 homodimer (G1) and ABCG5-ABCG8 heterodimer (G5G8), two members of the adeno

29 uction, whereas reductions in Gata4 diminish Abcg5/Abcg8 expression and biliary cholesterol excretion

30 ozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of s

31 This haplotype spans the ABCG5/ABCG8 genes, is carried by 1.8% of the islanders,

32 The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neu

33 re human disease Sitosterolemia, the role of ABCG5/ABCG8 in sterol trafficking and how newer data imp

34 and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenes

35 re involved on pathogenesis, and the role of ABCG5/ABCG8 may extend into other metabolic processes by

36 ac mice confirmed a functional defect in the ABCG5/ABCG8 transport system.

37 tion by regulating the expression of Mtp and Abcg5/Abcg8 via Shp and Gata4.

38 The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gall

39 is caused by a genetic defect of sterolins (ABCG5/ABCG8) mapped to the STSL locus.

40 irst, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol a

41 iting cholesterol biosynthesis and promoting ABCG5/ABCG8-mediated cholesterol excretion.

42 ozygous or compound heterozygous variants in ABCG5/ABCG8.

43 regulators of disease-associated transporter ABCG5/ABCG8.

44 Mice expressing no ABCG5 and ABCG8 (G5G8(-/-) mice) and their littermate co

45 ccumulation of plant sterols in mice lacking ABCG5 and ABCG8 (G5G8-/- mice) profoundly perturbs chole

46 ABCG5 and ABCG8 are both half-size transporters that hav

47 ABCG5 and ABCG8 are half-size ABC transporters that func

48 These data indicate that ABCG5 and ABCG8 are required for efficient secretion of

49 Thus Abcg5 and Abcg8 are required for LXR agonist-associated

50 The mature, glycosylated forms of ABCG5 and ABCG8 coimmunoprecipitated, consistent with he

51 ABCG5 and ABCG8 form a complex (G5G8) that opposes the a

52 ABCG5 and ABCG8 form a functional complex that limits di

53 ABCG5 and ABCG8 form heterodimers that limit absorption

54 Here we demonstrate that the ABCG5 and ABCG8 genes are direct targets of the oxystero

55 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and p

56 es with mice doubly transgenic for the human ABCG5 and ABCG8 genes rescued platelet counts and volume

57 hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mi

58 Purified ABCG5 and ABCG8 had very low ATPase activities (<5 nmol

59 the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 have recently been shown to cause the au

60 expressed recombinant, epitope-tagged mouse ABCG5 and ABCG8 in cultured cells.

61 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8(-/-)).

62 Overexpressing ABCG5 and ABCG8 in mice attenuates diet-induced atherosc

63 the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in patients with sitosterolemia suggests

64 These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vi

65 ession of NPC1L1 and increased expression of ABCG5 and ABCG8 in small intestine.

66 ndividual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been in

67 Higher hepatic messenger RNA expression of Abcg5 and Abcg8 in strain PERA/Ei correlates positively

68 rated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5

69 To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrup

70 the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 lead to sitosterolemia, a disorder chara

71 The ABC transporters ABCG5 and ABCG8 limit absorption and promote excretion o

72 n-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression.

73 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal a

74 Immunoelectron microscopy revealed ABCG5 and ABCG8 on the plasma membrane of these cells.

75 lts demonstrate that increased expression of ABCG5 and ABCG8 selectively drives biliary neutral stero

76 strain PERA/Ei), colocalizes with the genes Abcg5 and Abcg8 that encode the canalicular cholesterol

77 The addition of ABCG5 and ABCG8 to the growing list of LXR target genes

78 allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the s

79 Both ABCG5 and ABCG8 underwent N-linked glycosylation.

80 ligase, accelerated the degradation of both ABCG5 and ABCG8 via E3 activity-dependent manner.

81 When ABCG5 and ABCG8 were coexpressed, the attached sugars we

82 The Endo H-sensitive forms of ABCG5 and ABCG8 were confined to the endoplasmic reticul

83 lation in hepatic mRNA and protein levels of ABCG5 and ABCG8, and in hepatic mRNA levels of Niemann-P

84 Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and -2, respectivel

85 Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol abso

86 ol; it also upregulates liver and intestinal ABCG5 and ABCG8, helping to promote biliary and fecal ex

87 the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for both the increase in st

88 sion of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cho

89 To determine the site of action of ABCG5 and ABCG8, we expressed recombinant, epitope-tagge

90 in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and

91 riphosphate-binding cassette transporter G5 (ABCG5) and ABC transporter G8 (ABCG8).

92 ing cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), me

93 was accompanied by elevated jejunal ABCB1a, ABCG5, and ABCG8 expression, mediated by augmented level

94 ansporting polypeptide (NTCP), OATP1, OATP2, ABCG5, and ABCG8) in the liver.

95 ompletely known but involves the genes ABC1, ABCG5, and ABCG8, which are members of the ATP-binding c

96 lesterol transport or uptake (SCARB1, ABCA1, ABCG5, and LIPC), long-chain omega-3 fatty acid status (

97 significant down-regulation of BMI-1, ABCG2, ABCG5, and MDR1 expression and in a concomitant increase

98 in expression and increased levels of ABCG2, ABCG5, and MDR1.

99 Sitosterolemia induced in Abcg5- and Abcg8-deficient mice fed a high plant sterol

100 ATP binding cassette subfamily B member 11), Abcg5 (ATP-binding cassette [ABC] transporters subfamily

101 Expression levels of the jejunal Abcg5 (ATP-binding cassette transporter G5) and Abcg8, b

102 of the bile salt tauroursodeoxycholic acid, Abcg5 became fully rate-limiting for biliary cholesterol

103 ation status of ABCG5; rather it accelerated ABCG5 degradation in an E3 activity-dependent manner.

104 oprotein (HDL): Abcg5 ko < wild type < Sr-bI/Abcg5 dko < Sr-bI ko.

105 > Sr-bI ko (-16%) > Abcg5 ko (-75%) > Sr-bI/Abcg5 dko (-94%), all at least P < 0.05, while biliary b

106 almost 50% decrease in overall RCT in Sr-bI/Abcg5 dko compared with Abcg5 ko mice (P < 0.01).

107 In Sr-bI/Abcg5 dko plasma plant sterols were highest, while hepat

108 Using Sr-bI/Abcg5 double knockout mice (dko), the present study inve

109 Mutations in ABCG5 (encoding sterolin-1) or ABCG8 (encoding sterolin-

110 the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholester

111 ABCG5 (G5) and ABCG8 (G8) are ATP-binding cassette (ABC)

112 ABCG5 (G5) and ABCG8 (G8) are ATP-binding cassette half-

113 ATP-binding cassette transporters ABCG5 (G5) and ABCG8 (G8) form a heterodimer that transp

114 The ATP-binding cassette half-transporters ABCG5 (G5) and ABCG8 (G8) promote secretion of neutral s

115 Mutations in ABCG5 (G5) or ABCG8 (G8) cause sitosterolemia, an autoso

116 We found that ABCG5(-/-)/G8(-/-) and ABCG8 (-/-) mice displayed the sa

117 (3) H]sitostanol was detected in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice.

118 erol secretion and gallstones in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice.

119 tone characteristics in male wild-type (WT), ABCG5(-/-)/G8(-/-), and ABCG8 (-/-) mice fed a lithogeni

120 ate supported the highest ATPase activity in ABCG5/G8 (256 +/- 9 nmol min(-1) mg(-1)).

121 n ATP hydrolysis in Pichia pastoris purified ABCG5/G8 and found that they stimulated hydrolysis appro

122 er attenuated bile acid induction of hepatic Abcg5/g8 and gallbladder cholesterol content, suggesting

123 cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system.

124 nadate, BeFx, and AlFx effectively inhibited ABCG5/G8 at concentrations of 1 mM.

125 ic expression of CYP7alpha1, CYP27alpha1, or ABCG5/G8 between ABCA1-Tg and control mice.

126 ydrolysis approximately 20-fold in wild-type ABCG5/G8 but not in a hydrolysis-deficient mutant.

127 ary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is inv

128 Copurified ABCG5/G8 displayed low but significant ATPase activity w

129 efect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-knockout mice.

130 y promote an active conformation of purified ABCG5/G8 either by global stabilization of the transport

131 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns.

132 Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol

133 there was no change in bile acid synthesis, ABCG5/G8 expression, or hepatic cholesterol concentratio

134 agonist GW4064 or bile acids induced hepatic Abcg5/g8 expression.

135 Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into

136 ne FTO2B, LXR-dependent transcription of the ABCG5/G8 genes was cycloheximide-resistant, indicating t

137 ce, and two gallstone-associated variants in ABCG5/G8 have been identified in humans.

138 ying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.

139 Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma l

140 findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not

141 xclusion from the body, we fed wild-type and ABCG5/G8 knockout mice a diet enriched with plant sterol

142 -phytosterol diet was extremely toxic to the ABCG5/G8 knockout mice but had no adverse effects on wil

143 ABCG5/G8 knockout mice died prematurely and developed a

144 toxic effects of phytosterol accumulation in ABCG5/G8 knockout mice.

145 esterol markedly increased the expression of ABCG5/G8 mRNA in mouse liver and intestine.

146 from LXR agonist-treated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes

147 sterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr

148 dependent of the lithogenic mechanism of the ABCG5/G8 pathway.

149 formation, which works independently of the ABCG5/G8 pathway.

150 Although ABCG5/G8 plays a critical role in determining hepatic st

151 s by specific trapping of nucleotides in the ABCG5/G8 proteins.

152 udies demonstrated that bile acids increased ABCG5/G8 specific cholesterol efflux in cell models.

153 determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we gen

154 into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critic

155 The catalytic activity of copurified ABCG5/G8 was characterized in detail, demonstrating low

156 to bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol

157 binding cassette subfamily G member 5 and 8 (ABCG5/G8) and scavenger receptor class B type I (SR-BI)

158 transporters that function as heterodimers (ABCG5/G8) to reduce sterol absorption in the intestines

159 ate binding cassette subfamily G member 5/8 (ABCG5/G8).

160 We hypothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential f

161 ing alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR.

162 e-binding cassette (ABC) sterol transporter, Abcg5/g8, is Lith9 in mice, and two gallstone-associated

163 of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 d

164 rnative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary

165 ta demonstrate that (1) SR-BI contributes to ABCG5/G8-independent biliary cholesterol secretion under

166 pothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential for regulating

167 To elucidate the effect of the ABCG5/G8-independent pathway on cholelithogenesis, we in

168 The ABCG5/G8-independent pathway plays an important role in

169 cholesterol transport (RCT) independently of ABCG5/G8-mediated biliary cholesterol secretion, implyin

170 nsporter or by binding to a specific site on ABCG5/G8.

171 lesterol increase ATP hydrolysis in purified ABCG5/G8.

172 es to macrophage-to-feces RCT independent of Abcg5/g8.

173 regulated by TH, induces gene expression of ABCG5/G8.

174 -stimulated conditions is fully dependent on ABCG5/G8; and (3) Sr-bI contributes to macrophage-to-fec

175 erge, with published structures of ABCA1 and ABCG5/G8; these two proteins function in the reverse cho

176 enosine triphosphate-binding cassette G5/G8 [ABCG5/G8], scavenger receptor class B, member 1) and bil

177 ional FXR binding site was identified in the Abcg5 gene promoter.

178 ATP)-binding cassette subfamily G, member 5 (Abcg5) gene, alters a tryptophan codon (UGG) to a premat

179 One gene, ABCG5, had two nonsense mutations (Q16X and R446X).

180 (ATP-binding cassette transporters ABCA1 and ABCG5, hydroxymethylglutaryl-CoA synthase and the LDL re

181 Resequencing of ABCG5 in these carriers found a D450H missense mutation

182 er family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia.

183 a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patien

184 er family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitostero

185 fferences in high density lipoprotein (HDL): Abcg5 ko < wild type < Sr-bI/Abcg5 dko < Sr-bI ko.

186 llowing order: wild type > Sr-bI ko (-16%) > Abcg5 ko (-75%) > Sr-bI/Abcg5 dko (-94%), all at least P

187 patic plant sterols were lower compared with Abcg5 ko (P < 0.05).

188 overall RCT in Sr-bI/Abcg5 dko compared with Abcg5 ko mice (P < 0.01).

189 In polarized WIF-B cells, recombinant ABCG5 localized to the apical (canalicular) membrane whe

190 increased cholesterol secretion 3.1-fold in Abcg5(+/+) mice, whereas this response was severely blun

191 ion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice.

192 Basal biliary cholesterol secretion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice.

193 hereas this response was severely blunted in Abcg5(-/-) mice.

194 (1) mg(-)(1)), suggesting that expression of ABCG5 or ABCG8 alone yielded nonfunctional transporters.

195 osterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-

196 Mutations in either ABCG5 or ABCG8 cause sitosterolemia, a recessive disorde

197 5n-3 had no effect on the T1317 induction of ABCG5 or ABCG8 in the rat hepatoma cell line, FTO-2B.

198 ABCG5 or ABCG8 mutations can cause sitosterolemia, in wh

199 Mutations in either ABCG5 or ABCG8 result in an identical clinical phenotype

200 phosphate-binding cassette transporter genes ABCG5 or ABCG8 that result in accumulation of xenosterol

201 binding cassette subfamily G members 5 or 8 (ABCG5 or ABCG8) genes.

202 osterolemia is caused by mutations in either ABCG5 or ABCG8, but simultaneous mutations of these gene

203 TP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols int

204 sorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary st

205 Mice homozygous for disruption of Abcg5 (Abcg5(-/-) ) or Lxra (Lxra(-/-) ) and their wild-type co

206 ct on the LXR-regulated transcripts, CYP7A1, ABCG5, or ABCG8.

207 ing yielded two disease-associated variants: ABCG5-R50C (P = 4.94 x 10(-9) ) and ABCG8-D19H (P = 1.74

208 ight effect on the N-glycosylation status of ABCG5; rather it accelerated ABCG5 degradation in an E3

209 f ABCG8, a protein that heterodimerizes with ABCG5 to control sterol balance.

210 idiabetic effect by downregulating Abca1 and Abcg5 to inhibit hepatic cholesterol efflux, promoting l

211 d ATP-binding cassette subfamily G member 5 (Abcg5), upregulation of mRNA level of Glucose transporte